Extracorporeal CO2 removal is a highly promising support therapy for patients with hypercapnic respiratory failure but whose clinical implementation and patient benefit is hampered by high cost and highly specialized expertise required for safe use. Current approaches target removal of the gaseous CO2 dissolved in blood which limits their ease of clinical use as high blood flow rates are required to achieve physiologically significant CO2 clearance. Here, a novel hybrid approach in which a zero-bicarbonate dialysis is used to target removal of bicarbonate ion coupled to a gas exchange device to clear dissolved CO2, achieves highly efficiently total CO2 capture while maintaining systemic acid–base balance. In a porcine model of acute hypercapnic respiratory failure, a CO2-reduction of 61.4 ± 14.4 mL/min was achieved at a blood flow rate of 248 mL/min using pediatric-scale priming volumes. The dialyzer accounted for 81% of total CO2 capture with an efficiency of 33% with a minimal pH change across the entire circuit. This study demonstrates the feasibility of a novel hybrid CO2 capture approach capable of achieving physiologically significant CO2 removal at ultralow blood flow rates with low priming volumes while leveraging widely available dialysis platforms to enable clinical adoption.